Synthetic catalase/superoxide dismutase mimetics and methods for treating viral infections

ABSTRACT

The invention provides for the treatment of disorders related to viral infection, using salen manganese compounds.

The present application claims the benefit of U.S. provisionalapplication 61/558,137, filed Nov. 10, 2011, which is incorporated byreference herein in its entirety.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Research supporting this application was carried out by the UnitedStates of America as represented by the Secretary, Department of Healthand Human Services. The government has certain rights in the invention.

TECHNICAL FIELD

The invention is directed towards methods of treating viral infectionsusing salen manganese compounds, wherein such compounds provideprotection from oxidative damage.

BACKGROUND OF THE INVENTION

Molecular oxygen is an essential nutrient for nonfacultative aerobicorganisms including humans. Oxygen is used in many important ways,namely, as the terminal electronic acceptor in oxidativephosphorylation, in many dioxygenase reactions, including the synthesisof prostaglandins and of vitamin A from carotenoids, in a host ofhydroxylase reactions, including the formation and modification ofsteroid hormones, and in both the activation and the inactivation ofxenobiotics, including carcinogens.

The extensive P-450 system uses molecular oxygen in a host of importantcellular reactions. In a similar vein, nature employs free radicals in alarge variety of enzymic reactions.

Excessive concentrations of various forms of oxygen and of free radicalscan have serious adverse effects on living systems, including theperoxidation of membrane lipids, the hydroxylation of nucleic acidbases, and the oxidation of sulfhydryl groups and of other sensitivemoieties in proteins. If uncontrolled, mutations and cellular deathresult.

Biological antioxidants include well-defined enzymes, such as superoxidedismutase, catalase, selenium glutathione peroxidase, and phospholipidhydroperoxide glutathione peroxidase. Nonenzymatic biologicalantioxidants include tocopherols and tocotrienols, carotenoids,quinones, bilirubin, ascorbic acid, uric acid, and metal-bindingproteins. Various antioxidants, being both lipid and water soluble, arefound in all parts of cells and tissues, although each specificantioxidant often shows a characteristic distribution pattern. Theso-called ovothiols, which are mercaptohistidine derivatives, alsodecompose peroxides nonenzymatically.

Free radicals, particularly free radicals derived from molecular oxygen,are believed to play a fundamental role in a wide variety of biologicalphenomena. In fact, it has been suggested that much of what isconsidered critical illness may involve oxygen radical (“oxyradical”)pathophysiology (Zimmermen J J (1991) Chest 100: 189S). Oxyradicalinjury has been implicated in the pathogenesis of pulmonary oxygentoxicity, adult respiratory distress syndrome (ARDS), bronchopulmonarydysplasia, sepsis syndrome, and a variety of ischemia-reperfusionsyndromes, including myocardial infarction, stroke, cardiopulmonarybypass, organ transplantation, necrotizing enterocolitis, acute renaltubular necrosis, and other disease. Oxyradicals can react withproteins, nucleic acids, lipids, and other biological macromoleculesproducing damage to cells and tissues, particularly in the criticallyill patient.

Free radicals can originate from many sources, including aerobicrespiration, cytochrome P-450-catalyzed monooxygenation reactions ofdrugs and xenobiotics (e.g., trichloromethyl radicals, CCl₃, formed fromoxidation of carbon tetrachloride), and ionizing radiation. For example,when tissues are exposed to gamma radiation, most of the energydeposited in the cells is absorbed by water and results in scission ofthe oxygen-hydrogen covalent bonds in water, leaving a single electronon hydrogen and one on oxygen creating two radicals H. and .OH. Thehydroxyl radical, .OH, is the most reactive radical known in chemistry.It reacts with biomolecules and sets off chain reactions and caninteract with the purine or pyrimidine bases of nucleic acids. Indeed,radiation-induced carcinogenesis may be initiated by free radical damage(Breimer L H (1988) Brit. J. Cancer 57: 6). Also for example, the“oxidative burst” of activated neutrophils produces abundant superoxideradical, which is believed to be an essential factor in producing thecytotoxic effect of activated neutrophils. Reperfusion of ischemictissues also produces large concentrations of oxyradicals, typicallysuperoxide (Gutteridge J M C and Halliwell B (1990) Arch. Biochem.Biophys. 283: 223). Moreover, superoxide may be produced physiologicallyby endothelial cells for reaction with nitric oxide, a physiologicalregulator, forming peroxynitrite, ONOO⁻ which may decay and give rise tohydroxyl radical, .OH (Marletta M A (1989) Trends Biochem. Sci. 14: 488;Moncada et al. (1989) Biochem. Pharmacol. 38: 1709; Saran et al. (1990)Free Rad. Res. Commun. 10: 221; Beckman et al. (1990) Proc. Natl. Acad.Sci. (U.S.A.) 87: 1620). Additional sources of oxyradicals are “leakage”of electrons from disrupted mitochondrial or endoplasmic reticularelectron transport chains, prostaglandin synthesis, oxidation ofcatecholamines, and platelet activation.

Oxygen, though essential for aerobic metabolism, can be converted topoisonous metabolites, such as the superoxide anion and hydrogenperoxide, collectively known as reactive oxygen species (ROS). IncreasedROS formation under pathological conditions is believed to causecellular damage through the action of these highly reactive molecules onproteins, lipids, and DNA. During inflammation, ROS are generated byactivated phagocytic leukocytes; for example, during the neutrophil“respiratory burst”, superoxide anion is generated by the membrane-boundNADPH oxidase. ROS are also believed to accumulate when tissues aresubjected to ischemia followed by reperfusion.

Many free radical reactions are highly damaging to cellular components;they crosslink proteins, mutagenize DNA, and peroxidize lipids. Onceformed, free radicals can interact to produce other free radicals andnon-radical oxidants such as singlet oxygen (¹O2) and peroxides.Degradation of some of the products of free radical reactions can alsogenerate potentially damaging chemical species. For example,malondialdehyde is a reaction product of peroxidized lipids that reactswith virtually any amine-containing molecule. Oxygen free radicals alsocause oxidative modification of proteins (Stadtman E R (1992) Science257: 1220).

SUMMARY OF THE INVENTION

In one aspect, the invention provides a method of treating a disease ordisorder associated with viral infection in a subject, the methodcomprising the step of administering to the subject an effective amountof a compound of formula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In another aspect, the invention provides a method of treating a diseaseor disorder associated with viral infection in a subject, wherein thesubject is identified as being in need of suppression of oxidativestress, the method comprising the step of administering to the subjectan effective amount of a compound as described herein (e.g., formula I);or a pharmaceutically acceptable salt, ester or hydrate thereof.

In another aspect, the invention provides a method of treating a diseaseor disorder associated with viral infection in a subject, wherein thesubject is identified as being in need of a scavenger of reactive oxygenspecies or reactive nitrogen species, the method comprising the step ofadministering to the subject an effective amount of a compound asdescribed herein (e.g., formula I); or a pharmaceutically acceptablesalt, ester or hydrate thereof.

In another aspect, the invention provides a method for the prophylaxisor treatment of a viral infection in a subject, comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of a compound as described herein (e.g., formula I); or apharmaceutically acceptable salt, ester or hydrate thereof.

In another aspect, the invention provides a method of suppression ofoxidative stress in a subject, the method comprising the step ofadministering to the subject an effective amount of a compound asdescribed herein (e.g., formula I); or a pharmaceutically acceptablesalt, ester or hydrate thereof.

In another aspect, the invention provides a method of increasingcatalase/superoxide dismutase mimetic activity in a subject, the methodcomprising the step of administering to the subject an effective amountof a compound as described herein (e.g., formula I); or apharmaceutically acceptable salt, ester or hydrate thereof.

In another aspect, the invention provides a method of protecting frommitochondrial injury, the method comprising the step of administering tothe subject an effective amount of a compound as described herein (e.g.,formula I); or a pharmaceutically acceptable salt, ester or hydratethereof.

DETAILED DESCRIPTION OF THE INVENTION Brief Description of the Drawings

FIG. 1. Mice infected with a lethal dose of the 1918 virus and treatedday 3 to 10 post-exposure with the Salen-manganese catalase mimeticEUK-207 showed significantly increased survival and greatly lessenedlung pathology compared to vehicle treated controls.

FIG. 2. Salen-manganese treated mice showed greatly lessened lungpathology compared to vehicle treated controls that showed severenecrotizing bronchitis, bronchiolitis, alveolitis, edema and pulmonaryhemorrhage.

FIG. 3. High coverage viral sequence analysis further showed thatsalen-manganese drug treatment did not appear to exert any selectivepressure on the virus and no changes in the viral genome could bedetected demonstrating that drug treatment did not result in generationof resistance mutations.

METHODS OF TREATMENT

In one aspect, the invention provides a method of treating a disease ordisorder associated with viral infection in a subject, the methodcomprising the step of administering to the subject an effective amountof a compound of formula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In another aspect, the invention provides a method of treating a diseaseor disorder associated with viral infection in a subject, wherein thesubject is identified as being in need of suppression of oxidativestress, the method comprising the step of administering to the subjectan effective amount of a compound of formula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In one embodiment, the compound suppresses oxidative stress to therebytreat viral infection.

In another aspect, the invention provides a method of treating a diseaseor disorder associated with viral infection in a subject, wherein thesubject is identified as being in need of a scavenger of reactive oxygenspecies or reactive nitrogen species, the method comprising the step ofadministering to the subject an effective amount of a compound offormula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In one embodiment, the compound scavenges a reactive oxygen species orreactive nitrogen species to thereby treat viral infection.

In various embodiments, the disease or disorder is influenza, pandemicinfluenza virus, a retrovirus, rhabdovirus, filovirus, hepatitis type A,hepatitis type B, hepatitis type C, varicella, adenovirus, human herpesvirus, herpes simplex type I (HSV-I), herpes simplex type II (HSV-II),rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytialvirus, papilloma virus, papova virus, cytomegalovirus, echinovirus,arbovirus, hantavirus, coxsachie virus, mumps virus, measles virus,rubella virus, polio virus, human immunodeficiency virus type I (HIV-I),and human immunodeficiency virus type II (HIV-II), any picornaviridae,enteroviruses, caliciviridae, any of the Norwalk group of viruses,togaviruses, alphaviruses, flaviviruses, such as Dengue virus,coronaviruses, rabies virus, Marburg viruses, Ebola viruses,parainfluenza virus, orthomyxoviruses, bunyaviruses, arenaviruses,reoviruses, rotaviruses, orbiviruses, human T cell leukemia virus typeI, human T cell leukemia virus type II, simian immunodeficiency virus,lentiviruses, polyomaviruses, parvoviruses, Epstein-Barr virus, humanherpesvirus-6, cercopithecine herpes virus 1 (B virus), varicella zostervirus, orthopox virus, West Nile Virus, avian influenza viruses, orpoxviruses.

In a further embodiment, the disease or disorder is influenza, pandemicinfluenza virus, hepatitis type A, hepatitis type B, hepatitis type C,herpes simplex type I (HSV-I), herpes simplex type II (HSV-II), mumpsvirus, measles virus, rubella virus, polio virus, Epstein-Barr virus,varicella zoster virus, orthopox virus, human immunodeficiency virustype I (HIV-I), or human immunodeficiency virus type II (HIV-II).

In another further embodiment, the disease or disorder is influenza orpandemic influenza virus.

In other embodiments, the disorder treated is orthopox, selected fromvariola major and minor, vaccinia, smallpox, cowpox, camelpox andmonkeypox.

Additional diseases or disorders that can be treated or prevented by thepresent invention include, but are not limited to, those caused byinfluenza virus, human respiratory syncytial virus, pseudorabies virus,pseudorabies virus II, swine rotavirus, swine parvovirus, bovine viraldiarrhea virus, Newcastle disease virus, swine flu virus, swine fluvirus, foot and mouth disease virus, hog colera virus, swine influenzavirus, African swine fever virus, infectious bovine rhinotracheitisvirus, infectious laryngotracheitis virus, La Crosse virus, neonatalcalf diarrhea virus, Venezuelan equine encephalomyelitis virus, puntatoro virus, murine leukemia virus, mouse mammary tumor virus, equineinfluenza virus or equine herpesvirus, bovine respiratory syncytialvirus or bovine parainfluenza virus.

Probably the most common viral infections are those of the upperrespiratory airway (i.e., for example, nose, throat, etc.). Theseinfections include sore throat, sinusitis, and the common cold.Influenza is a viral respiratory infection. In small children, virusesalso commonly cause croup and inflammation of the windpipe (i.e., forexample, laryngotracheobronchitis) or other airways deeper inside thelungs. Respiratory infections are more likely to cause severe symptomsin infants, older people, and people with a lung or heart disorder.

One aspect of the invention is a method for the treatment or prophylaxisof influenza in a patient to reduce or prevent symptoms associated withinfluenza virus infection. The patient can be human or any other animalsusceptible to influenza infection (e.g. domestic animals such as catsand dogs; livestock and farm animals such as horses, cows, pigs,chickens, etc.). Medical care standards are used to determine that thata patient is likely infected with influenza virus or is at risk ofexposure to influenza virus. The influenza virus can be an A or B virus.In specific embodiments, the virus is an influenza A virus (e.g. H1N1,H1N2, H2N2, H3N2, H5N1, H7N7, H9N2, etc.).

Some viruses (i.e., for example, rabies virus, West Nile virus, andseveral different encephalitis viruses) infect the nervous system. Viralinfections also develop in the skin, sometimes resulting in warts orother blemishes.

Other common viral infections are caused by herpes viruses. Eightdifferent herpes viruses infect people, including but not limited to,herpes simplex virus type 1, herpes simplex virus type 2, andvaricella-zoster virus cause infections that produce blisters on theskin or mucus membranes. Another herpes virus, Epstein-Barr virus,causes infectious mononucleosis. Cytomegalovirus is a cause of seriousinfections in newborns and in people with a weakened immune system.Cytomegalovirus can also produce symptoms similar to infectiousmononucleosis in people with a healthy immune system. Human herpesviruses 6 and 7 cause a childhood infection called roseola infantum.Human herpes virus 8 has been implicated as a cause of cancer (Kaposi'ssarcoma) in people with AIDS.

All of the herpes viruses cause lifelong infection because the virusremains within its host cell in a dormant (latent) state. Sometimes thevirus reactivates and produces further episodes of disease. Reactivationmay occur rapidly or many years after the initial infection.

In addition, the present invention features methods of using compoundsof the present invention or pharmaceutically acceptable salts thereof totreat HCV infection. The methods comprise administering to an HCVpatient in need thereof an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof.

Therapeutic methods of the invention can also include the step ofidentifying that the subject is in need of treatment of diseases ordisorders described herein, e.g., identifying that the subject is inneed of treatment for a viral infection. The identification can be inthe judgment of a subject or a health professional and can be subjective(e.g., opinion) or objective (e.g., measurable by a test or a diagnosticmethod). Tests for viral infection such as influenza or HIV infectionare known in the art and include polymerase chain reaction-based(PCR-based) amplification and detection of viral RNA; Western blotdetection of antibodies; agglutination assays for antibodies;ELISA-based detection of antigens; and line immunoassay (LIA). In eachof these methods, a sample of biological material, such as blood,plasma, semen, or saliva, is obtained from the subject to be tested.Thus, the methods of the invention can include the step of obtaining asample of biological material (such as a bodily fluid) from a subject;testing the sample to determine the presence or absence of viralinfection such as HIV infection, HIV particles, or HIV nucleic acids;and determining whether the subject is in need of treatment according tothe invention.

The methods delineated herein can further include the step of assessingor identifying the effectiveness of the treatment or prevention regimenin the subject by assessing the presence, absence, increase, or decreaseof a marker, including a marker or diagnostic measure of a viralinfection such as infection, replication, viral load, or expression ofan infection marker; preferably this assessment is made relative to ameasurement made prior to beginning the therapy. Such assessmentmethodologies are known in the art and can be performed by commercialdiagnostic or medical organizations, laboratories, clinics, hospitalsand the like. As described above, the methods can further include thestep of taking a sample from the subject and analyzing that sample. Thesample can be a sampling of cells, genetic material, tissue, or fluid(e.g., blood, plasma, sputum, etc.) sample. The methods can furtherinclude the step of reporting the results of such analyzing to thesubject or other health care professional. The method can furtherinclude additional steps wherein (such that) the subject is treated forthe indicated disease or disease symptom.

In another aspect, the invention provides a method for the prophylaxisor treatment of a viral infection in a subject, comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of a compound of formula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following:

optionally substituted alkyl, optionally substituted alkenyl oroptionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In certain embodiments, M is a metal, preferably a transition metal. Incertain embodiments, M is selected from Mn, Cr, Fe, Zn, Cu, Ni, Co, Ti,V, Ru and Os. In various embodiments, A is an anion. In variousembodiments, A is halogen or an organic anion. In a further embodiments,A is PF₆, (Aryl)₄, BF₄, B(Aryl)₄, halogen, acetate, acetyl, formyl,formate, triflate, tosylate or, alternatively, A is an oxygen atomtypically bound via a double bond to the metal, i.e., M.

In certain embodiments, the invention provides a method as describedabove, wherein the compound is of formula II,

wherein:

M is Mn;

A is halogen, PF₆, (Aryl)₄, BF₄, B(Aryl)₄, acetate, acetyl, formyl,formate, propionate, formate, triflate, or tosylate;

X₁ and X₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ are each independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a fusedaryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

Q₁ and Q₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein the phenyl rings to which Z is attached are notconnected; or

Z is —(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—;

each R₆ is independently O, NR_(x), S(O)_(t), alkenyl, alkynyl, aryl,heteroaryl, cyclic, or heterocyclic;

R_(x) is H or optionally substituted alkyl;

n is 0, 1, or 2;

each q is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;

each r is independently 0 or 1; and

t is 0, 1, or 2;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In another embodiment, Z is absent wherein the phenyl rings to which Zis attached are not connected.

In other embodiments, Z is —(CH₂)_(q)—, —(CQ₁Q₂)_(q)-, or Z is—(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—; wherein each R₆ isindependently 0, alkenyl, aryl, or cyclic.

In another embodiment, the invention provides a method as describedabove, wherein the compound is of formula III,

wherein:

M is Mn;

A is halogen, PF₆, (Aryl)₄, BF₄, B(Aryl)₄, acetate, acetyl, formyl,formate, propionate, formate, triflate, or tosylate;

X₁ and X₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), or —NR_(A)R_(B); each of which is optionally substituted;

Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ are each independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —OR_(A), or —NR_(A)R_(B); each of which is optionallysubstituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), —C(O)OR_(A), —C(O)R_(A), or —NR_(A)R_(B); each of which isoptionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a fusedaryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

Q₁ and Q₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), or —NR_(A)R_(B); each of which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; and

n is 0, 1, or 2;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In another embodiment, the invention provides a method as describedabove, wherein the compound is of formula II,

wherein:

M is Mn;

A is halogen, PF₆, (Aryl)₄, BF₄, B(Aryl)₄, acetate, acetyl, formyl,formate, propionate, formate, triflate, or tosylate;

X₁ and X₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), or —NR_(A)R_(B); each of which is optionally substituted;

Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ are each independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —OR_(A), or —NR_(A)R_(B); each of which is optionallysubstituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), —C(O)OR_(A), —C(O)R_(A), or —NR_(A)R_(B); each of which isoptionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a fusedaryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

Q₁ and Q₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), or —NR_(A)R_(B); each of which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is —(CH₂)_(q)—, —(CQ₁Q₂)_(q)-, or—(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—;

each R₆ is independently 0, aryl, or cyclic;

n is 0, 1, or 2;

each q is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

each r is independently 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In a further embodiment, X₁ and X₂ are each independently hydrogen,halogen, alkyl, —OR_(A), or —NR_(A)R_(B); each of which is optionallysubstituted.

In another embodiment, X₁ and X₂ are each independently hydrogen or—OR_(A).

In various embodiments, Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ are eachindependently hydrogen, halogen, alkyl, —OR_(A), or —NR_(A)R_(B); eachof which is optionally substituted. In a further embodiment, Y₁, Y₂, Y₃,Y₄, Y₅, and Y₆ are each independently hydrogen or halogen. In a furtherembodiment, Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ are each independently hydrogenor —OR_(A). In a further embodiment, Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ are eachindependently hydrogen or —NR_(A)R_(B).

In other embodiments, n is 0 and R₁, R₂, R₃ and R₄ are independentlyhydrogen, —OR_(A), or —NR_(A)R_(B).

In various embodiments, n is 0 and R₁ is covalently linked to R₃ or R₄to form a 5 membered or 6 membered fused aryl, heteroaryl, cycloalkyl,or heterocycloalkyl. In a further embodiment, the ring is a cyclohexylring, a benzene ring or a pyridine ring.

In certain embodiments, n is 1 and Q₁ and Q₂ are each independentlyhydrogen, alkyl, —OR_(A), or —NR_(A)R_(B).

In other embodiments, Z is

—CH₂.CH₂.O—CH₃.CH₂—; —CH₂.CH₂.O—CH₂.CH₂.O—CH₂.CH₂—;

—CH₂.O—CH₂—; —CH₂.CH═CH—CH₂—;

In another embodiments, the invention provides a method as describedabove, wherein the compound is of formula III:

wherein,

A is halogen, PF₆, (Aryl)₄, BF₄, B(Aryl)₄, acetate, acetyl, formyl,formate, propionate, formate, triflate, or tosylate;

X₁ and X₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), or —NR_(A)R_(B); each of which is optionally substituted;

Y₃, Y₄, Y₅, and Y₆ are each independently hydrogen, halogen, alkyl,aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —OR_(A), or —NR_(A)R_(B); each of which is optionallysubstituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), —C(O)OR_(A), —C(O)R_(A), or —NR_(A)R_(B); each of which isoptionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a fusedaryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

Q₁ and Q₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—OR_(A), or —NR_(A)R_(B); each of which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent; or —(CH₂)_(q)—, —(CQ₁Q₂)_(q)-, or—(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—;

each R₆ is independently O, aryl, or cyclic;

each q is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

each r is independently 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.]]

In one embodiment, R₁, and R₃ are each independently H, phenyl, benzyl,O-benzyl, or —C(O)OR_(A).

In other embodiments, R₁ is covalently linked to R₃ or R₄ to form acyclohexyl.

In various embodiments, the compound is selected from

Advantages of the methods of the invention include the low cost of thesyntheses of the compounds used, the stability of the compounds, lowtoxicity, aerosolizable formulation, targets host response pathways,little development of resistance, and broad specificity.

In another aspect, the invention provides a method of suppression ofoxidative stress in a subject, the method comprising the step ofadministering to the subject an effective amount of a compound offormula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In another aspect, the invention provides a method of increasingcatalase/superoxide dismutase mimetic activity in a subject, the methodcomprising the step of administering to the subject an effective amountof a compound of formula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Z is absent whereinring A and ring B, to which Z is attached, are not connected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In another aspect, the invention provides a method of protecting frommitochondrial injury, the method comprising the step of administering tothe subject an effective amount of a compound of formula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, ester or hydrate thereof.

In certain embodiments, the compound is identified in a screening assay.

In a further embodiment, the screening assay is an assay for cell death,an assay for oxidative injury to the mitochondria or other cellularcomponents, an assay for expression of proteins modulated by oxidativestress, or an assay for oxidative post-translational modification ofproteins, lipids or nucleic acids

In another further embodiment, the compound has a IC₅₀ for inhibitingless than about 5 micromolar.

In yet another aspect, the present invention provides methods of usingthe compounds of the present invention (e.g., formula I) to preventand/or to treat free radical-associated damage or freeradical-associated diseases. More particularly, the present inventionprovides methods and compositions for the following: (1) preventingischemic/reoxygenation injury in a patient; (2) preserving organs fortransplant; (3) protecting normal tissues from free radical-induceddamage consequent to exposure to ionizing radiation (UV light, gammaradiation, etc.) and/or chemotherapy (e.g., with bleomycin); (4)protecting cells and tissues from free radical-induced injury consequentto exposure to xenobiotic compounds that form free radicals, eitherdirectly or as a consequence of monooxygenation through the cytochromeP-450 system; (5) enhancing cryopreservation of cells, tissues, organs,and organisms by increasing the viability of recovered specimens; and(6) prophylactic administration to prevent, for example, carcinogenesis,cellular senescence, cataract formation, formation of malondialdehydeadducts, HIV pathology and macromolecular crosslinking, such as collagencrosslinking.

The present invention also provides compounds having peroxidase activityand, therefore, capable of serving as effective peroxidase replacements.These compounds are useful as drugs for the prevention of manypathological conditions, including but not limited to neoplasia,apoptosis of somatic cells, skin aging, cataracts, and the like; and asanti-oxidants for scavenging H₂O₂ and other peroxides. The presentinvention also provides methods and pharmaceutical compositions of thesecompounds.

The present invention also concerns a method of reducing H₂O₂ and/orother peroxides which comprises contacting H₂O₂ and/or other peroxideswith a suitable amount of any of the compounds of the inventioneffective to reduce H₂O₂ and/or other peroxides. Additionally, theinvention provides a method of treating a peroxide-induced condition ina subject which comprises administering to the subject an amount of anyof the compounds of the invention effective to reduce peroxide in asubject and thereby treat the peroxide-induced condition. Further, theinvention provides a pharmaceutical composition which comprises anamount of any of the compounds of the invention effective to reduceperoxide in a subject with a peroxide-induced condition and apharmaceutically acceptable carrier. Further, the invention provides amethod of treating a peroxide-induced condition in a subject, e.g. ahuman subject, which comprises administering, to the subject an amountof a compound described herein (e.g., formula I) effective to reduceperoxide in the subject and thereby treat the peroxide-inducedcondition. It is worthy to point out at this time that theadministration of the compound to the subject may be effected by meansother than those listed herein.

Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formulaI,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following: optionally substituted alkyl, optionally substitutedalkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

or a pharmaceutically acceptable salt, solvate or hydrate thereof, incombination with a pharmaceutically acceptable carrier or excipient.

In one embodiment, the invention provides a pharmaceutical composition,in combination with an anti-viral agent.

In another aspect, the invention provides a method for identifying aprotein which has its expression changed by a viral infection, themethod comprising:

a) treating a subject with a compound of the invention (e.g., formula I)under conditions suitable for modulation of the amount of the protein;and

b) detecting modulation of the amount of the protein after treatmentwith the compound of the invention (e.g., formula I).

In another aspect, the invention provides a kit comprising an effectiveamount of a compound of formula I,

wherein:

M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni;

A is halogen or an organic anion;

ring A and ring B are each independently an aryl or heteroaryl;

each X is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

each Y is independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted;

Y₁ and Y₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or

R₁ or R₂ may be covalently linked to one of R₃ or R₄ to form a ring;

each Q₁ and Q₂ are independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted;

R_(A) and R_(B) are each independently selected at each occurrence fromthe following:

optionally substituted alkyl, optionally substituted alkenyl oroptionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Z is absent wherein ring A and ring B, to which Z is attached, are notconnected; or

Z is a bridging group;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 0 or 1;

in unit dosage form, together with instructions for administering thecompound to a subject suffering from or susceptible to a viral disease.

In accordance with the foregoing objects, in one aspect of the inventionpharmaceutical compositions are provided which have potent antioxidantand/or free radical scavenging properties and function as in vivoantioxidants. The pharmaceutical compositions of the invention comprisean efficacious dosage of a compound described herein (e.g., formula I).These pharmaceutical compositions possess the activity of dismutatingsuperoxide (i.e., superoxide dismutase activity) and, advantageously,also converting hydrogen peroxide to water (i.e., catalase activity).The pharmaceutical compositions are effective at reducing pathologicaldamage related to formation of oxyradicals such as superoxide andperoxides and other free radical species. In another aspect, theinvention provides a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention (any ofthe formulae presented herein), or a pharmaceutically acceptable salt,solvate or hydrate thereof thereof, in combination with apharmaceutically acceptable carrier or excipient.

Yet another aspect of the present invention is a process of making anyof the compounds delineated herein employing any of the synthetic meansdelineated herein. The pharmaceutical compositions of the presentinvention comprise a therapeutically effective amount of a compound ofthe present invention formulated together with one or morepharmaceutically acceptable carriers. As used herein, the term“pharmaceutically acceptable carrier” means a non-toxic, inert solid,semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type. The pharmaceutical compositions ofthis invention can be administered to humans and other animals orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, or drops),buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups,and elixirs. In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art such as, forexample, water, alcohol or other solvents, solubilizing agents andemulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, polysorbate, dimethylformamide, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor, and sesameoils), mono- or di-glycerides, glycerol, tetrahydrofurfuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof. Besides inert diluents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents,antioxidants, sweetening, flavoring, and perfuming agents. The liquiddosage form can also be encapsulated in a gelatin capsule, wherein acompound of the present invention can be dissolved in a pharmaceuticallyacceptable carrier containing, for example, one or more solubilizatingagents (e.g., polysorbate 80 and mono and diglycerides), and othersuitable excipients (e.g., an antioxidants such as ascorbyl palmitate,or a sweetening or flavoring agent).

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Immediate release forms are also contemplated by the presentinvention.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings, release controlling coatings and other coatings well known inthe pharmaceutical formulating art. In such solid dosage forms theactive compound may be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,tableting lubricants and other tableting aids such a magnesium stearateand microcrystalline cellulose. In the case of capsules, tablets andpills, the dosage forms may also comprise buffering agents.

Preferably, a compound of the invention is formulated in a soliddispersion, where the compound can be molecularly dispersed in a matrixwhich comprises a pharmaceutically acceptable, hydrophilic polymer. Thematrix may also contain a pharmaceutically acceptable surfactant.Suitable solid dispersion technology for formulating a compound of theinvention includes, but is not limited to, melt extrusion, spray drying,or solvent evaporization.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention, adisorder is treated in a subject, such as a human or another animal, byadministering to the subject a therapeutically effective amount of acompound of the invention (or a pharmaceutically acceptable salt, esteror prodrug thereof), in such amounts and for such time as is necessaryto achieve the desired result. The term “therapeutically effectiveamount” of a compound of the invention, as used herein, means asufficient amount of the compound so as to decrease the subject'ssymptoms. As is well understood in the medical arts a therapeuticallyeffective amount of a compound of this invention will be at a reasonablebenefit/risk ratio applicable to any medical treatment.

Compounds of the invention also may be administered as a “cocktail”formulation, i.e., coordinated administration of one or more compoundsof the invention together with one or more other active therapeutics.

For an antiviral therapy, one or more compounds of the inventionincluding those of Formula I may be administered in coordination with aregime of one or more other antiviral agents such as reversetranscriptase inhibitors such as dideoxynucleosides, e.g. zidovudine(AZT), 2′,3′-dideoxyinosine (ddI) and 2′,3′-dideoxycytidine (ddC),lamivudine (3TC), stavudine (d4T), and TRIZIVIR(abacavir+zidovudine+lamivudine), nonnucleosides, e.g., efavirenz(DMP-266, DuPont Pharmaceuticals/Bristol Myers Squibb), nevirapine(Boehringer Ingleheim), and delaviridine (Pharmacia-Upjohn), TATantagonists such as Ro 3-3335 and Ro 24-7429, protease inhibitors, e.g.,indinavir (Merck), ritonavir (Abbott), saquinavir (Hoffmann LaRoche),nelfinavir (Agouron Pharmaceuticals), 141 W94 (Glaxo-Wellcome),atazanavir (Bristol Myers Squibb), amprenavir (GlaxoSmithKline),fosamprenavir (GlaxoSmithKline), tipranavir (Boehringer Ingleheim),KALETRA (lopinavir+ritonavir, Abbott), and other agents such as9-(2-hydroxyethoxymethyl)guanine (acyclovir), interferon, e.g.,alpha-interferon, interleukin II, and phosphonoformate (Foscarnet), orentry inhibitors, e.g., T20 (enfuvirtide, Roche/Trimeris) or UK-427,857(maraviroc, Pfizer). Because many of these drugs are directed todifferent targets, e.g., viral integration, a synergistic may resultwith this combination.

In one embodiment, one or more compounds of the invention includingthose of the formulae herein are used in conjunction with one or moretherapeutic agents useful for treatment or prevention of HIV, a symptomassociated with HIV infection, or other disease or disease symptom suchas a secondary infection or unusual tumor such as herpes,cytomegalovirus, Kaposi's sarcoma and Epstein-Barr virus-relatedlymphomas among others, that can result in HIV immuno-compromisedsubjects.

In certain embodiments of the invention, one or more compounds of theinvention including those of Formula I are used in conjunction with astandard HIV antiviral treatment regimens. In another aspect, thetreatment methods herein include administration of a so-called HIV-drug“cocktail” or combination therapy, wherein a combination of reversetranscriptase inhibitor(s) and HIV protease inhibitor(s) isco-administered.

For antiviral therapies, in a particular aspect, the compounds of theinvention can be administered to HIV infected individuals or toindividuals at high risk for HIV infection, for example, those havingsexual relations with an HIV infected partner, intravenous drug users,etc.

Compounds of the present invention can be administered in combinationwith one or more agents to treat or prevent influenza a virus,comprising a M2 inhibitor, IMP dehydrogenase inhibitor, RNA polymeraseinhibitor, influenza-specific interfering oligonucleotide, andneuraminidase inhibitor.

Preferably each drug in the combination is active at a different phasein the influenza virus life cycle. For example, influenza virusadsorption inhibitors and M2 inhibitors are active at the beginning ofthe lifecycle; IMP dehydrogenase inhibitors and RNA polymeraseinhibitors are active at the middle of the lifecycle; and interferingoligonucleotides and neuramimidase inhibitors are active at the end ofthe lifecycle.

Examples of M2 inhibitors include aminoadamantane compounds such asamantadine (1-amino-adamantane), rimantadine(1-(1-aminoethyl)adamantane),spiro[cyclopropane-1,2′-adamantan]-2-amine,spiro[pyrrolidine-2,2′-adamantane], spiro[piperidine-2,2′-adamantane],2-(2-adamantyl)piperidine, 3-(2-adamantyl)pyrrolidine,2-(1-adamantyl)piperidine, 2-(1-adamantyl)pyrrolidine, and2-(1-adamantyl)-2-methyl-pyrrolidine; and M2-specific monoclonalantibodies (see e.g. US 20050170334; and Zebedee and Lamb, J. Virol.(1988) 62:2762-72). In a preferred embodiment, one of the antiviralagents in the triple combination is amantadine or rimantadine.

Examples of IMP dehydrogenase inhibitors include ribavirin, viramidine(a prodrug of ribavirin), and merimepodib (VX-497; see e.g. Markland etal., Antimicrob Agents Chemother. (2000) 44:859-66).

The term RNA polymerase inhibitor refers to an antiviral agent thatinhibits the polymerase, protease, and/or endonuclease activity of theviral RNA polymerase complex or one of its subunits (i.e. PB1, PB2 andPA). Exemplary RNA polymerase inhibitors include antiviral nucleosideanalogs such as ribavirin, viramidine,6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705),2′-deoxy-2′-fluoroguanosine, pyrazofurin, 3-deazaguanine, carbodine (seee.g. Shannon et al., Antimicrob Agents Chemother. (1981) 20:769-76), andcyclopenenyl cytosine (see e.g. Shigeta et al., Antimicrob AgentsChemother. (1988) 32:906-11); and the endonuclease inhibitor flutimide(see e.g. Tomassini et al., Antimicrob Agents Chemother. (1996)40:1189-93). In a preferred embodiment, one of the antiviral agents inthe triple combination is ribavirin or viramidine.

Examples of influenza-specific interfering oligonucleotides includesiRNAs (see e.g. Zhou et al., Antiviral Res. (2007) 76; 186-93),antisense oligonucleotides, phosphorothioate oligonucleotides, ribozymes(see e.g. U.S. Pat. No. 6,258,585 to Draper), morpholino oligomers andpeptide nucleic acids (see e.g. Schubert and Kurreck, Handb ExpPharmacol. (2006) 173:261-87).

Examples of neuraminidase inhibitors include oseltamivir, oseltamivircarboxylate (GS4071; see e.g. Eisenberg et al., Antimicrob AgentsChemother. (1997) 41:1949-52), zanamivir, peramivir (RWJ-27021;BXC-1812, BioCryst), 2,3-didehydro-2-deoxy-N-acetylneuraminic acid(DANA), 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA),A-322278, and A-315675 (see U.S. Pat. No. 6,455,571 to Maring et al, andKati et al., Antimicrob Agents Chemother. (2002) 46:1014-21). In apreferred embodiment, one of the antiviral agents in the triplecombination is oseltamivir, peramivir, or zanamivir.

Other agents to be administered in combination with a compound of thepresent invention include any agent or combination of agents thatinhibit the replication of other viruses for co-infected individuals.These agents include but are not limited to therapies for disease causedby hepatitis B (HBV) infection or therapies for disease caused by humanimmunodeficiency virus (HIV) infection.

In another further embodiment, the other agent or agents are nucleosideHIV reverse transcriptase inhibitors, non-nucleoside HIV reversetranscriptase inhibitors, HIV protease inhibitors, HIV fusioninhibitors, HIV attachment inhibitors, HIV entry inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, orHIV integrase inhibitors or combinations thereof.

In various embodiments, the invention provides a method described abovewherein the step of administering the compound comprises administeringthe compound orally, topically, parentally, intravenously orintramuscularly.

In various embodiments, the invention provides a method described abovewherein the subject is a human.

The term “inhibitory amount” of a compound of the present inventionmeans a sufficient amount to decrease the viral disorder in a biologicalsample or a subject. It is understood that when said inhibitory amountof a compound of the present invention is administered to a subject itwill be at a reasonable benefit/risk ratio applicable to any medicaltreatment as determined by a physician. The term “biological sample(s),”as used herein, means a substance of biological origin, which may beintended for administration to a subject. Examples of biological samplesinclude, but are not limited to, blood and components thereof such asplasma, platelets, subpopulations of blood cells and the like; organssuch as kidney, liver, heart, lung, and the like; sperm and ova; bonemarrow and components thereof; or stem cells.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.1 mg/kg to about 500 mg/kg, alternatively fromabout 1 to about 50 mg/kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

The total daily inhibitory dose of the compounds of this inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 50 mg/kg body weight or more usuallyfrom 0.1 to 25 mg/kg body weight. Single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. In oneembodiment, treatment regimens according to the present inventioncomprise administration to a patient in need of such treatment fromabout 10 mg to about 1000 mg of the compound(s) of this invention perday in single or multiple doses. In another embodiment, the treatmentregimen comprises administration to a patient in need of such treatmentfrom about 25 mg to about 6000 mg of a compound(s) of this invention perday in single or multiple doses. For instance a compound of the presentinvention can be administered to a patient twice a day with a totaldaily dose of 4000, 4200, 4400, 4600, 4800 or 5000 mg.

In one embodiment, the patient is administered a compound as describedabove in an amount to maintain a plasma concentration between 0.1 to10.0 μg/ml, 0.5 to 8 μg/ml, 0.5 to 5.0 μ.g/ml, 1 to 6 μg/ml, 1 to 4μg/ml, 2 to 6 μg/ml, 2 to 4 μg/ml, 0.01-2 μg/ml, or 0.2-2 μg/ml for atleast 48 continuous hours. In a specific embodiment, the patient isadministered a compound as described above in an amount to maintain aplasma concentration between 0.1 to 3.0 μg/ml, 0.1 to 1.5 μg/ml, or 0.3to 1.5 μg/ml for at least 48 continuous hours.

In another embodiment, the patient is administered a compound asdescribed above parenterally or orally in an amount of 5 to 500 mg/day,20 to 250 mg/day, 100 to 800 mg/day, 100 to 600 mg/day, 200 to 700mg/day, or 200 to 500 mg/day. The patient is administered the compoundas described above parenterally or orally in an amount of 50 to 2000mg/day, 50 to 1600 mg/day, 100 to 1200 mg/day, 400 to 800 mg/day, 50 to600 mg/day, 75 to 500 mg/day, or 75 to 200 mg/day.

In a further embodiment, the patient is administered a compound asdescribed above by intravenous infusion at a rate of 1 to 50 mg/hr, 3 to40 mg/hr, or 5 to 30 mg/hr for at least 48 continuous hours. In aspecific embodiment, the patient is administered the compound asdescribed above by intravenous infusion at a rate of 5 to 200 mg/hr, 10to 150 mg/hr, 15 to 100, or 20 to 80 mg/hr for at least 48 continuoushours.

In another embodiment, the therapeutically effective amount is fromabout 0.01 mg to about 5,000 mg per day.

The current method for diagnosis of disease, determining exposure tobiological materials such as pathogens, or monitoring immunizationstatus varies depending on the specific assay. Some methods employ an invivo assay. Others require a biological sample, such as blood or serum,to be obtained and tested. Tests performed usually are one of thenon-homogeneous type diagnostic methods such as enzyme-linkedimmunosorbant assay (hereinafter “ELISA”), radioimmunoassay (hereinafter“RIA”), or agglutination. All are surface-binding, heterogeneous assaysand require the antigen of interest to interact with a surface toachieve success, often at the expense of high non-specific binding andloss of specificity.

The embodiments described herein improve upon previously reportedimmunoassays by providing a totally liquid environment encompassing allsteps of the method.

Biological Data

There is great need for the development of novel drug therapies forhighly pathogenic influenza virus infections. Drugs that target hostresponse pathways represent a major advance because of the greatlydecreased potential for development of antiviral resistance. The 1918pandemic influenza virus resulted in 40-60 million deaths worldwide.

Studies in animal models have demonstrated that 1918 virus infectionresults in uncontrolled inflammatory responses hypothesized to lead toimmunopathogenic effects, severe lung pathology and lethality. However,no studies have shown that aberrant immune responses are responsible forthe extreme pathogenicity of the 1918 influenza virus. Here, it is shownthat mice infected with a lethal dose of the 1918 virus and treated day3 to 10 post-exposure with the Salen-manganese catalase mimetic EUK-207showed significantly increased survival and greatly lessened lungpathology compared to vehicle treated controls. In three independentstudies, mice (n=95 total) infected with a lethal challenge dose of thehighly virulent 1918 pandemic influenza virus and treated from day 3 to10 post-exposure with a Salen-manganese catalase mimetic showedsignificantly increased survival (40-50%) compared to vehiclealone-treated animals (n=55 total). See FIG. 1. Drug treatment wasperformed post-exposure by intraperitoneal injection of 1.5 mg/kg/day ofEUK-207 diluted in water and given from days 3 to 10 post-infection.

Salen-manganese treated mice also showed greatly lessened lung pathologycompared to vehicle treated controls that showed severe necrotizingbronchitis, bronchiolitis, alveolitis, edema and pulmonary hemorrhage(FIG. 2).

High-throughput next generation RNA sequencing analysis of host lunggene expression showed salen-manganese treatment resulted in a markeddecrease in expression of inflammatory response, cell death and celldeath related genes, as well as a significant increase in lung repairresponses.

High coverage viral sequence analysis further showed thatsalen-manganese drug treatment did not appear to exert any selectivepressure on the virus and no changes in the viral genome could bedetected demonstrating that drug treatment did not result in generationof resistance mutations (FIG. 3). Our results demonstrate that drugstargeting the host inflammatory response and immune cell killing areefficacious in greatly limiting lung pathology and death during a highlypathogenic influenza viral infection. These results demonstrate thatinhibition of reactive oxygen species using salen-manganese compoundsproduced during highly virulent viral reduces inflammatory and celldeath responses; while promoting tissue repair and host survival.Additionally, the use of these compounds to modulate the hostinflammatory response are used in the identification of biomarkersassociated with both severe disease and survival from infection.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.The number of carbon atoms in a hydrocarbyl substituent can be indicatedby the prefix “C_(x)—C_(y),” where x is the minimum and y is the maximumnumber of carbon atoms in the substituent. Likewise, a C_(x) chain meansa hydrocarbyl chain containing x carbon atoms.

The term “virus” refers to obligate, ultramicroscopic, intracellularparasites incapable of autonomous replication (i.e., replicationrequires the use of the host cell's machinery). Viruses are exemplifiedby, but not limited to, adenovirus, rhinovirus, human papilloma virus,human immunodeficiency virus, hepatitis virus, Newcastle disease virus,cardiovirus, corticoviridae, cystoviridae, epstein-barr virus,filoviridae, hepadnviridae, hepatitis virus, herpes virus, influenzavirus, inoviridae, iridoviridae, metapneumovirus, orthomyxoviridae,papovavirus, parainfluenza virus, paramyxoviridae, parvoviridae,polydnaviridae, poxyviridae, reoviridae, respiratory syncytial virus,rhabdoviridae, semliki forest virus, tetraviridae, toroviridae, vacciniavirus, and vesicular stomatitis virus. “Virus” also includes an animalvirus that is not a plus-strand RNA virus as exemplified by, but notlimited to, Arenaviridae, Baculoviridae, Bimaviridae, Bunyaviridae,Cardiovirus, Corticoviridae, Cystoviridae, Epstein-Ban virus,Filoviridae, Hepadnviridae, Hepatitis virus, Herpesviridae, Influenzavirus, Inoviridae, Iridoviridae, Metapneumovirus, Orthomyxoviridae,Papovaviru, Paramyxoviridae, Parvoviridae, Polydnaviridae, Poxyviridae,Reoviridae, Rhabdoviridae, Semliki Forest virus, Tetraviridae,Toroviridae, Vaccinia virus, Vesicular stomatitis virus.

The term “respiratory virus” as used herein, refers to any virus capableof infecting pulmonary tissues (i.e., for example, lung tissue). Forexample, a respirator virus includes, but is not limited to, influenza,parainfluenza, adenovirus, rhinovirus, herpes simplex virus, respiratorysyncytial virus, hantavirus, or cytomegalovirus.

As used herein, “influenza” refers to a contagious respiratory illnessor infection caused by a number of viruses. Symptoms of the flu includeextreme tiredness, muscle aches, chills, cough, fever, headache, sorethroat, runny or stuffy nose, nausea, vomiting, and diarrhea. Influenzaviruses are divided into three types, designated A, B, and C. Influenzatypes A and B are responsible for epidemics of respiratory illness thatoccur almost every winter and are often associated with increased ratesof hospitalization and death. Type C infection usually causes either avery mild respiratory illness or no symptoms at all; it does not causeepidemics and does not have the severe public health impact of influenzatypes A and B.

As used herein, an “antioxidant” is a substance that, when present in amixture or structure containing an oxidizable substrate biologicalmolecule, significantly delays or prevents oxidation of the substratebiological molecule. Antioxidants can act by scavenging biologicallyimportant reactive free radicals or other reactive oxygen species (e.g.,H₂O₂, OH, HOCl, ferryl, peroxyl, peroxynitrite, and alkoxyl), or bypreventing their formation, or by catalytically converting the freeradical or other reactive oxygen species to a less reactive species. Anantioxidant salen-transition metal complex of the invention generallyhas detectable ROS scavenging activity. A salen-transition metal complexof the invention has antioxidant activity if the complex, when added toa cell culture or assay reaction, produces a detectable decrease in theamount of a free radical, such as superoxide, or a nonradical reactiveoxygen species, such as hydrogen peroxide, as compared to a parallelcell culture or assay reaction that is not treated with the complex. Therelative amount of free radical species is often determined by detectionof a secondary indicator (e.g., an oxidized substrate; peroxidizedlipid, reduced NBT, cytochrome c). Suitable concentrations (i.e.,efficacious dose) can be determined by various methods, includinggenerating an empirical dose-response curve, predicting potency andefficacy of a congener by using QSAR methods or molecular modeling, andother methods used in the pharmaceutical sciences. Since oxidativedamage is generally cumulative, there is no minimum threshold level (ordose) with respect to efficacy, although minimum doses for producing adetectable therapeutic or prophylactic effect for particular diseasestates can be established. Antioxidant salen metal complexes of theinvention may have glutathione peroxidase activity or peroxidaseactivity in general.

As used herein, a “salen-transition metal complex” refers to a compoundhaving a structure according to Formula I or any of the formulae herein.In Formula I, the axial ligand (A) is typically a halogen or an organicanion (such as acetate, propionate, butyrate or formate). The metal (M)is typically a transition metal (such as Mn, Mg, Co, Fe, Cu, Zn, V, Cr,and Ni; preferably Mn or V and, more preferably, Mn; wherein the typicaloxidation state is +3).

As used herein, “free radical-associated disease” refers to apathological condition of an individual that results at least in partfrom the production of or exposure to free radicals, particularlyoxyradicals, and other reactive oxygen species. It is evident to thoseof skill in the art that most pathological conditions aremultifactorial, in that multiple factors contributing to the diseasestate are present, and that assigning or identifying the predominantcausal factor(s) for any individual pathological condition is frequentlyextremely difficult. For these reasons, the term “free radicalassociated disease” encompasses pathological states that are recognizedin the art as being conditions wherein damage from free radicals orreactive oxygen species is believed to contribute to the pathology ofthe disease state, or wherein administration of a free radical inhibitor(e.g., desferrioxamine), scavenger (e.g., tocopherol, glutathione), orcatalyst (e.g., SOD, catalase) is shown to produce a detectable benefitby decreasing symptoms, increasing survival, or providing otherdetectable clinical benefits in treating or preventing the pathologicalstate. For example but not limitation, the disease states discussedherein are considered free radical-associated diseases (e.g., ischemicreperfusion injury, inflammatory diseases, systemic lupus erythematosus,myocardial infarction, stroke, traumatic hemorrhage, brain and spinalcord trauma, Crohn's disease, autoimmune diseases (e.g., rheumatoidarthritis, diabeates), cataract formation, uveitis, emphysema, gastriculcers, oxygen toxicty, neoplasia, undesired cell apoptosis, radiationsickness, and other pathological states disclosed herein, such astoxemia and acute lung injury). Such diseases can include“apoptisus-related ROS,” which refers to reactive oxygen species (e.g.,O₂—, HOOH) which damage critical cellular components (e.g., lipidperoxidation) in cells stimulated to undergo apoptosis, suchapoptosis-related ROS may be formed in a cell in response to anapoptotic stimulus and/or produced by non-respiratory electrontranspoort chains (i.e., other than ROS produced by oxidativephosphorylation).

As used herein the terms “SOD mimetic,” “SOD mimic,” “superoxidedismutase mimetic,” and “superoxide catalyst” refer to compounds thathave detectable catalytic activity for the scavenging of superoxide asdetermined by assay. Generally, an SOD mimetic possesses at least about0.001 percent of the SOD activity of human Mn-SOD or Zn, Cu-SOD, on aweight basis, as determined by standard assay methods such as forexample the SOD assay used herein below.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, “C₁-C₆haloalkyl” means a C₁-C₆alkyl substituentwherein at least one hydrogen radical is replaced with a halogenradical.

If a linking element in a depicted structure is “absent” or “a bond”,then the left element in the depicted structure is directly linked tothe right element in the depicted structure. For example, if a chemicalstructure is depicted as X-(L)_(n)-Y wherein L is absent or n is 0, thenthe chemical structure is X—Y. In certain instances, if a linkingelement in a depicted structure is “absent”, then the left element inthe depicted structure is not connected to the right element in thedepicted structure. For example, if a chemical structure is depicted as

wherein Z is absent, then the chemical structure is one where the leftring and the right ring are not connected.

The term “alkyl” as used herein, refers to a saturated, straight- orbranched-chain hydrocarbon radical. For example, “C₁-C₈ alkyl” containsfrom one to eight carbon atoms. Examples of alkyl radicals include, butare not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals and the like.

The term “alkenyl” as used herein, denotes a straight- or branched-chainhydrocarbon radical containing one or more double bonds. For example,“C₂-C₈ alkenyl” contains from two to eight carbon atoms. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.

The term “alkynyl” as used herein, denotes a straight- or branched-chainhydrocarbon radical containing one or more triple bonds. For example,“C₂-C₈ alkynyl” contains from from two to eight carbon atoms.Representative alkynyl groups include, but are not limited to, forexample, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.

The term “cycloalkyl” denotes a monovalent group derived from amonocyclic or polycyclic saturated carbocyclic ring compound. Examplesof cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyland the like. The terms “carbocycle” or “carbocyclic” or “carbocyclyl”refer to a saturated (e.g., “cycloalkyl”), partially saturated (e.g.,“cycloalkenyl” or “cycloalkynyl”) or completely unsaturated (e.g.,“aryl”) ring system containing zero heteroatom ring atom. A carbocyclylmay be, without limitation, a single ring, or two or more fused rings,or bridged or spiro rings. A carbocyclyl may contain, for example, from3 to 10 ring members (i.e., C₃-C₁₀-carbocyclyl, such asC₃-C₁₀cycloalkyl). A substituted carbocyclyl may have either cis ortrans geometry. Representative examples of carbocyclyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl,cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl,cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl,1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, bicyclodecanyl,anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”),decalinyl, and norpinanyl and the like. A carbocyclyl group can beattached to the parent molecular moiety through any substitutable carbonatom of the group.

The term “aryl” refers to an aromatic carbocyclyl containing from 6 to14 carbon ring atoms. Non-limiting examples of aryls include phenyl,naphthalenyl, anthracenyl, and indenyl and the like. An aryl group canbe connected to the parent molecular moiety through any substitutablecarbon atom of the group.

The term “heteroaryl” means an aromatic heterocyclyl typicallycontaining from 5 to 18 ring atoms. A heteroaryl may be a single ring,or two or more fused rings. Non-limiting examples of five-memberedheteroaryls include imidazolyl; furanyl; thiophenyl (or thienyl orthiofuranyl); pyrazolyl; oxazolyl; isoxazolyl; thiazolyl; 1,2,3-,1,2,4-, 1,2,5-, and 1,3,4-oxadiazolyl; and isothiazolyl. Non-limitingexamples of six-membered heteroaryls include pyridinyl; pyrazinyl;pyrimidinyl; pyridazinyl; and 1,3,5-, 1,2,4-, and 1,2,3-triazinyl.Non-limiting examples of 6/5-membered fused ring heteroaryls includebenzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl,purinyl, and anthranilyl. Non-limiting examples of 6/6-membered fusedring heteroaryls include quinolinyl; isoquinolinyl; and benzoxazinyl(including cinnolinyl and quinazolinyl).

The term “heterocycloalkyl” refers to a non-aromatic 3-, 4-, 5-, 6- or7-membered ring or a bi- or tri-cyclic group fused system, where atleast one of the ring atoms is a heteroatom, and where (i) each5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms mayoptionally be oxidized, (iii) the nitrogen heteroatom may optionally bequaternized, and (iv) any of the above rings may be fused to a benzenering. Representative heterocycloalkyl groups include, but are notlimited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, andtetrahydrofuryl and the like.

The terms “heterocyclic” or “heterocycle” or “heterocyclyl” refer to asaturated (e.g., “heterocycloalkyl”), partially unsaturated (e.g.,“heterocycloalkenyl” or “heterocycloalkynyl”) or completely unsaturated(e.g., “heteroaryl”) ring system, where at least one of the ring atomsis a heteroatom (i.e., nitrogen, oxygen or sulfur), with the remainingring atoms being independently selected from the group consisting ofcarbon, nitrogen, oxygen and sulfur. A heterocyclyl group can be linkedto the parent molecular moiety via any substitutable carbon or nitrogenatom in the group, provided that a stable molecule results. Aheterocyclyl may be, without limitation, a single ring. Non-limitingexamples of single-ring heterocyclyls include furanyl, dihydrofuranyl,pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazoly,pyranyl, dihydropyranyl, pyridinyl, piperidinyl, pyridazinyl,pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, isoxazinyl,oxazolidinyl, isoxazolidinyl, oxathiazinyl, oxadiazinyl, morpholinyl,azepinyl, oxepinyl, thiepinyl, or diazepinyl. A heterocyclyl may alsoinclude, without limitation, two or more rings fused together, such as,for example, naphthyridinyl, thiazolpyrimidinyl, thienopyrimidinyl,pyrimidopyrimidinyl, or pyridopyrimidinyl. A heterocyclyl may compriseone or more sulfur atoms as ring members; and in some cases, the sulfuratom(s) is oxidized to SO or SO₂. The nitrogen heteroatom(s) in aheterocyclyl may or may not be quaternized, and may or may not beoxidized to N-oxide. In addition, the nitrogen heteroatom(s) may or maynot be N-protected.

The terms “optionally substituted”, “optionally substituted alkyl,”“optionally substituted “optionally substituted alkenyl,” “optionallysubstituted alkynyl”, “optionally substituted carbocyclic,” “optionallysubstituted aryl”, “optionally substituted heteroaryl,” “optionallysubstituted heterocyclic,” and any other optionally substituted group asused herein, refer to groups that are substituted or unsubstituted byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with typical substituents including, but not limited to:

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic,

—F, —Cl, —Br, —I,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino,-diarylamino, -diheteroarylamino,

—O-alkyl, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocyclic,

—C(O)-alkyl, —C(O)-alkenyl, —C(O)-alkynyl, —C(O)-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —C(O)-heterocycloalkyl,

—CONH₂, —CONH-alkyl, —CONH-alkenyl, —CONH-alkynyl, —CONH-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,

—OCO₂-alkyl, —OCO₂-alkenyl, —OCO₂-alkynyl, —OCO₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH-alkyl,—OCONH-alkenyl, —OCONH-alkynyl, —OCONH-cycloalkyl, —OCONH-aryl,—OCONH-heteroaryl, —OCONH-heterocycloalkyl,

—NHC(O)-alkyl, —NHC(O)-alkenyl, —NHC(O)-alkynyl, —NHC(O)-cycloalkyl,—NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl,—NHCO₂-alkyl, —NHCO₂-alkenyl, —NHCO₂-alkynyl, —NHCO₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH-alkyl, —NHC(O)NH-alkenyl, —NHC(O)NH-alkenyl,—NHC(O)NH-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH-alkyl,—NHC(S)NH-alkenyl, —NHC(S)NH-alkynyl, —NHC(S)NH-cycloalkyl,—NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl,—NHC(NH)NH₂, —NHC(NH)NH-alkyl, —NHC(NH)NH—-alkenyl, —NHC(NH)NH-alkenyl,—NHC(NH)NH-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)-alkyl, —NHC(NH)-alkenyl,—NHC(NH)-alkenyl, —NHC(NH)-cycloalkyl, —NHC(NH)-aryl,—NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl,

—C(NH)NH-alkyl, —C(NH)NH-alkenyl, —C(NH)NH-alkynyl, —C(NH)NH-cycloalkyl,—C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocycloalkyl,

—S(O)-alkyl, —S(O)-alkenyl, —S(O)-alkynyl, —S(O)-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH-alkyl,—SO₂NH-alkenyl, —SO₂NH-alkynyl, —SO₂NH-cycloalkyl, —SO₂NH-aryl,—SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,

—NHSO₂-alkyl, —NHSO₂-alkenyl, —NHSO₂-alkynyl, —NHSO₂-cycloalkyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocycloalkyl,

—CH₂NH₂, —CH₂SO₂CH₃, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S— alkynyl, —S—cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

It is understood that the aryls, heteroaryls, carbocycles, heterocycles,alkyls, and the like can be further substituted.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be either a patient or a healthy human.

The term “alkylamino” refers to a group having the structure—N(R_(a)R_(b)), where R_(a) and R_(b) are independent H or alkyl.

The term “silyl” as used herein refers to organometallic substituents,wherein at least one silicon atom is linked to at least one carbon atom;an example of a silyl substituent is the trimethylsilyl substituent,(CH₃)₃Si—.

The term “fatty acid ester,” as used herein, refers to a substituentthat is derived from a fatty acid by removal of a hydrogen. Whenpresent, the fatty acid esters typically occupy no more than twosubstituent positions and are usually identical. Examples of fatty acidsfrom which the fatty acid esters can be derived include palmitoleic,oleic, petroselenic, vaccenic, punicic, parinaric, gadoleic, cetoleic,linoleic, linolenic, arachidonic, lauric, myristic, palmitic, stearic,eicosanoic, and docosanoic.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts, or saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, or magnesium salts, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,sulfonate and aryl sulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988);Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975); and Bernard Testa & Joachim Mayer,“Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry AndEnzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containingpharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

As used herein, “solvate” refers to the physical association of acompound of the invention with one or more solvent molecule, whetherorganic or inorganic. This physical association often includes hydrogenbonding. In certain instances, the solvate is capable of isolation, forexample, when one or more solvate molecules are incorporated in thecrystal lattice of the crystalline solid.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent invention. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this invention may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not to limit the scope of the invention. Thefollowing examples can be prepared according to the schemes as describedabove, or according to the synthetic steps as described below. Variouschanges and modifications to the disclosed embodiments will be apparentto those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

The chemical structures herein contain certain —NH—, —NH₂ (amino) and—OH (hydroxyl) groups where the corresponding hydrogen atom(s) may notexplicitly appear; however they are to be read as —NH—, —NH₂ or —OH asthe case may be.

Example 1 Treatment of Viral Infection with Salen Manganese Compounds

Mice were infected with a lethal dose of the 1918 virus and treated day3 to 10 post-exposure with the Salen-manganese catalase mimetic EUK-207.Drug treatment was performed post-exposure by intraperitoneal injectionof 1.5 mg/kg/day of EUK-207 diluted in water and given from days 3 to 10post-infection. Results are provided in FIG. 1.

Example 2 RNA Isolation and Next Generation Sequencing

Lungs were collected at 8 dpi with influenza and total RNA was isolatedfrom whole mouse lungs of 3 individual mice in each group byhomogenization of (10% w/v) in Trizol (Invitrogen) followed bychloroform extraction and isopropanol precipitation. RNA quality wasassessed using a BioAnalyzer (Agilent Technologies, CA). Equal amount oftotal RNA from each mouse were pooled together for experimental orcontrol group. mRNA selection, library preparation and sequencing wasperformed according to Illumina mRNA-seq sample preparation kitspecifications. Briefly, mRNA was selected using oligo(dT) probes andthen fragmented using heat treatment. cDNA was synthesized using randomprimers, modified and enriched for attachment to the Illumina flowcell.The cDNA fragment sizes of the libraries were ˜250 bp. We sequenced ontwo flowcells of 6 lanes each with 36-cycle paired-end runs. Eachflowcell contained 3 lanes of EUK treated samples and 3 lanes of vehicletreated samples. In total of 12 lanes, more than 635 million reads of atotal of >22 GB of sequence were generated. All three un-filteredpaired-end lanes of sequence have been deposited as a series with theaccession number GSE#### at NCBI's GEO database. Reads were mapped tobowtie index of mouse genome (UCSC version mm9) downloaded from Centerfor Bioinformatics and Computational Biology, University of Marylandwebsite (http://bowtie-bio.sourceforge.net/index.shtml) using Tophat(release 1.0.14) (http://tophat.cbcb.umd.edu/) and the published 1918H1N1 influenza virus genome using a Genomatix Genome Mining Station(Munich, Germany). Overall gene expression level in terms of Reads PerKilobase per Million mapped reads (RPKM) (reference 2) were calculatedby Cufflink package (release 0.8.2) (http://cufflinks.cbcb.umd.edu/).Differential expressed genes between EUK treated and vehicle treatedsample were identified by Cuffdiff function from Cufflink package(release 0.8.2) (http://cufflinks.cbcb.umd.edu/). The final set ofdifferential expressed genes was the overlapped data set identified inboth runs by Cuffdiff. We used the default options supplied with thesesoftware packages in our analyses except for Tophat mapping using -r250-mate-std-dev 30 and Cufflinks/Cuffdiff calling using -m 250-s 30.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended with be encompassed by the following claims.

1. A method of treating a disease or disorder associated with viralinfection in a subject, the method comprising the step of administeringto the subject an effective amount of a compound of formula I,

wherein: M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni; A is halogen or anorganic anion; ring A and ring B are each independently an aryl orheteroaryl; each X is independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; each Y is independently hydrogen,halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester,acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A),—SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; Y₁ and Y₂are each independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted; R₁, R₂, R₃ and R₄ are independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or R₁ or R₂ may be covalently linkedto one of R₃ or R₄ to form a ring; each Q₁ and Q₂ are independentlyhydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fattyacid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A),—SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; R_(A) andR_(B) are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Z is absent whereinring A and ring B, to which Z is attached, are not connected; or Z is abridging group; n is 0, 1, or 2; m is 0, 1, or 2; and p is 0 or 1; or apharmaceutically acceptable salt, ester or hydrate thereof.
 2. A methodof treating a disease or disorder associated with viral infection in asubject, wherein the subject is identified as being in need ofsuppression of oxidative stress, the method comprising the step ofadministering to the subject an effective amount of a compound offormula I,

wherein: M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni; A is halogen or anorganic anion; ring A and ring B are each independently an aryl orheteroaryl; each X is independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; each Y is independently hydrogen,halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester,acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A),—SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; Y₁ and Y₂are each independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted; R₁, R₂, R₃ and R₄ are independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or R₁ or R₂ may be covalently linkedto one of R₃ or R₄ to form a ring; each Q₁ and Q₂ are independentlyhydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fattyacid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A),—SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; R_(A) andR_(B) are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Z is absent whereinring A and ring B, to which Z is attached, are not connected; or Z is abridging group; n is 0, 1, or 2; m is 0, 1, or 2; and p is 0 or 1; or apharmaceutically acceptable salt, ester or hydrate thereof.
 3. Themethod of claim 2, wherein the compound suppresses oxidative stress tothereby treat viral infection.
 4. A method of treating a disease ordisorder associated with viral infection in a subject, wherein thesubject is identified as being in need of a scavenger of reactive oxygenspecies or reactive nitrogen species, the method comprising the step ofadministering to the subject an effective amount of a compound offormula I,

wherein: M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni; A is halogen or anorganic anion; ring A and ring B are each independently an aryl orheteroaryl; each X is independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; each Y is independently hydrogen,halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester,acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A),—SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; Y₁ and Y₂are each independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted; R₁, R₂, R₃ and R₄ are independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or R₁ or R₂ may be covalently linkedto one of R₃ or R₄ to form a ring; each Q₁ and Q₂ are independentlyhydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fattyacid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A),—SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; R_(A) andR_(B) are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Z is absent whereinring A and ring B, to which Z is attached, are not connected; or Z is abridging group; n is 0, 1, or 2; m is 0, 1, or 2; and p is 0 or 1; or apharmaceutically acceptable salt, ester or hydrate thereof. 5.(canceled)
 6. The method of claim 1, wherein the disease or disorder isinfluenza, pandemic influenza virus, a retrovirus, rhabdovirus,filovirus, hepatitis type A, hepatitis type B, hepatitis type C,varicella, adenovirus, human herpes virus, herpes simplex type I(HSV-I), herpes simplex type II (HSV-II), rinderpest, rhinovirus,echovirus, rotavirus, respiratory syncytial virus, papilloma virus,papova virus, cytomegalovirus, echinovirus, arbovirus, hantavirus,coxsachie virus, mumps virus, measles virus, rubella virus, polio virus,human immunodeficiency virus type I (HIV-I), and human immunodeficiencyvirus type II (HIV-II), any picornaviridae, enteroviruses,caliciviridae, a Norwalk group of viruses, togaviruses, alphaviruses,flaviviruses, Dengue virus, coronaviruses, rabies virus, Marburgviruses, Ebola viruses, parainfluenza virus, orthomyxoviruses,bunyaviruses, arenaviruses, reoviruses, rotaviruses, orbiviruses, humanT cell leukemia virus type I, human T cell leukemia virus type II,simian immunodeficiency virus, lentiviruses, polyomaviruses,parvoviruses, Epstein-Barr virus, human herpesvirus-6, cercopithecineherpes virus 1 (B virus), varicella zoster virus, orthopox virus, WestNile Virus, avian influenza viruses, or poxviruses. 7-8. (canceled)
 9. Amethod for the prophylaxis or treatment of a viral infection in asubject, comprising administering to a subject in need of such treatmenta therapeutically effective amount of a compound of formula I,

wherein: M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni; A is halogen or anorganic anion; ring A and ring B are each independently an aryl orheteroaryl; each X is independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; each Y is independently hydrogen,halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester,acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A),—SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; Y₁ and Y₂are each independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted; R₁, R₂, R₃ and R₄ are independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or R₁ or R₂ may be covalently linkedto one of R₃ or R₄ to form a ring; each Q₁ and Q₂ are independentlyhydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fattyacid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A),—SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; R_(A) andR_(B) are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Z is absent whereinring A and ring B, to which Z is attached, are not connected; or Z is abridging group; n is 0, 1, or 2; m is 0, 1, or 2; and p is 0 or 1; or apharmaceutically acceptable salt, ester or hydrate thereof.
 10. Themethod of claim 1, wherein the compound is of formula II,

wherein: M is Mn; A is halogen, PF₆, (Aryl)₄, BF₄, B(Aryl)₄, acetate,acetyl, formyl, formate, propionate, formate, triflate, or tosylate; X₁and X₂ are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; Y₁, Y₂, Y₃, Y₄, Y_(s), and Y₆ areeach independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted; R₁, R₂, R₃ and R₄ are independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or R₁ or R₂ may be covalently linkedto one of R₃ or R₄ to form a fused aryl, heteroaryl, cycloalkyl, orheterocycloalkyl; Q₁ and Q₂ are each independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; R_(A) and R_(B) are eachindependently selected at each occurrence from the following: optionallysubstituted alkyl, optionally substituted alkenyl or optionallysubstituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selectedfrom O, S, or N; optionally substituted aryl; optionally substitutedheteroaryl; optionally substituted heterocyclic; optionally substitutedcarbocyclic; or hydrogen; Z is absent wherein the phenyl rings to whichZ is attached are not connected to each other; or Z is—(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—(CQ₁Q₂)_(q)-(R₆)_(r)—; each R₆ isindependently O, NR_(x), S(O)_(t), alkenyl, alkynyl, aryl, heteroaryl,cyclic, or heterocyclic; R_(x) is H or optionally substituted alkyl; nis 0, 1, or 2; each q is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;each r is independently 0 or 1; and t is 0, 1, or 2; or apharmaceutically acceptable salt, ester or hydrate thereof.
 11. Themethod of claim 10, wherein Z is absent wherein the phenyl rings towhich Z is attached are not connected to each other.
 12. The method ofclaim 10, wherein Z is —(CH2)q-, —(CQ1Q2)q-, or Z is—(R6)r-(CQ1Q2)q-(R6)r-(CQ1Q2)q-(R6)r-; wherein each R6 is independentlyO, alkenyl, aryl, or cyclic.
 13. The method of claim 10, wherein thecompound is of formula III,

wherein: M is Mn; A is halogen, PF6, (Aryl)4, BF4, B(Aryl)₄, acetate,acetyl, formyl, formate, propionate, formate, triflate, or tosylate; X1and X2 are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—ORA, or —NRARB; each of which is optionally substituted; Y1, Y2, Y3,Y4, Y5, and Y6 are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—ORA, or —NRARB; each of which is optionally substituted; R1, R2, R3 andR4 are independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —ORA, —C(O)ORA,—C(O)RA, or —NRARB; each of which is optionally substituted; or R1 or R2may be covalently linked to one of R3 or R4 to form a fused aryl,heteroaryl, cycloalkyl, or heterocycloalkyl; Q1 and Q2 are eachindependently hydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl,silyl, fatty acid ester, acyloxy, aralkyl, —ORA, or —NRARB; each ofwhich is optionally substituted; RA and RB are each independentlyselected at each occurrence from the following: optionally substitutedalkyl, optionally substituted alkenyl or optionally substituted alkynyl,each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;optionally substituted aryl; optionally substituted heteroaryl;optionally substituted heterocyclic; optionally substituted carbocyclic;or hydrogen; and n is 0, 1, or 2; or a pharmaceutically acceptable salt,ester or hydrate thereof.
 14. The method of claim 10, wherein thecompound is of formula II,

wherein: M is Mn; A is halogen, PF6, (Aryl)₄, BF4, B(Aryl)₄, acetate,acetyl, formyl, formate, propionate, formate, triflate, or tosylate; X1and X2 are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—ORA, or —NRARB; each of which is optionally substituted; Y1, Y2, Y3,Y4, Y5, and Y6 are each independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—ORA, or —NRARB; each of which is optionally substituted; R1, R2, R3 andR4 are independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —ORA, —C(O)ORA,—C(O)RA, or —NRARB; each of which is optionally substituted; or R1 or R2may be covalently linked to one of R3 or R4 to form a fused aryl,heteroaryl, cycloalkyl, or heterocycloalkyl; Q1 and Q2 are eachindependently hydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl,silyl, fatty acid ester, acyloxy, aralkyl, —ORA, or —NRARB; each ofwhich is optionally substituted; RA and RB are each independentlyselected at each occurrence from the following: optionally substitutedalkyl, optionally substituted alkenyl or optionally substituted alkynyl,each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;optionally substituted aryl; optionally substituted heteroaryl;optionally substituted heterocyclic; optionally substituted carbocyclic;or hydrogen; Z is —(CH2)q-, —(CQ1Q2)q-, or—(R6)r-(CQ1Q2)q-(R6)r-(CQ1Q2)q-(R6)r-; each R6 is independently 0, aryl,or cyclic; n is 0, 1, or 2; each q is independently 0, 1, 2, 3, 4, 5, 6,7, or 8; and each r is independently 0 or 1; or a pharmaceuticallyacceptable salt, ester or hydrate thereof.
 15. The method of claim 13 orclaim 14, wherein X1 and X2 are each independently hydrogen, halogen,alkyl, —ORA, or —NRARB; each of which is optionally substituted.
 16. Themethod of claim 15, wherein X1 and X2 are each independently hydrogen or—ORA. 17-25. (canceled)
 26. The method of claim 1, wherein the compoundis selected from


27. A method of suppression of oxidative stress in a subject, the methodcomprising the step of administering to the subject an effective amountof a compound of formula I,

wherein: M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni; A is halogen or anorganic anion; ring A and ring B are each independently an aryl orheteroaryl; each X is independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; each Y is independently hydrogen,halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester,acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A),—SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; Y₁ and Y₂are each independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted; R₁, R₂, R₃ and R₄ are independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or R₁ or R₂ may be covalently linkedto one of R₃ or R₄ to form a ring; each Q₁ and Q₂ are independentlyhydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fattyacid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A),—SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; R_(A) andR_(B) are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Z is absent whereinring A and ring B, to which Z is attached, are not connected; or Z is abridging group; n is 0, 1, or 2; m is 0, 1, or 2; and p is 0 or 1; or apharmaceutically acceptable salt, ester or hydrate thereof, or A methodof increasing catalase/superoxide dismutase mimetic activity in asubject, the method comprising the step of administering to the subjectan effective amount of a compound of formula I,

wherein: M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni; A is halogen or anorganic anion; ring A and ring B are each independently an aryl orheteroaryl; each X is independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; each Y is independently hydrogen,halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester,acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A),—SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A)C(O)OR_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; Y₁ and Y₂are each independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A),—N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A),—C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted; R₁, R₂, R₃ and R₄ are independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or R₁ or R₂ may be covalently linkedto one of R₃ or R₄ to form a ring; each Q₁ and Q₂ are independentlyhydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fattyacid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A),—SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; R_(A) andR_(B) are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Z is absent whereinring A and ring B, to which Z is attached, are not connected; or Z is abridging group; n is 0, 1, or 2; m is 0, 1, or 2; and p is 0 or 1; or apharmaceutically acceptable salt, ester or hydrate thereof, or A methodof protecting from mitochondrial injury, the method comprising the stepof administering to the subject an effective amount of a compound offormula I,

wherein: M is Mn, Mg, Co, Cu, Zn, V, Cr or Ni; A is halogen or anorganic anion; ring A and ring B are each independently an aryl orheteroaryl; each X is independently hydrogen, halogen, alkyl, aryl,heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl,—CN, —CF₃, —N₃—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); each ofwhich is optionally substituted; each Y is independently hydrogen,halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester,acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A),—SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A)C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; Y₁ and Y₂are each independently hydrogen, halogen, alkyl, aryl, heterocyclic,heteroaryl, silyl, fatty acid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃,—NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)R_(A),—N(R_(A)), —S(O₂)NR_(A)R_(B), —C(O)R_(A), —(C(O)R_(A), —C(O)NR_(A)R_(B),or —N(RA)C(O)RB; or —N(R_(A))C(O)R_(B); each of which is optionallysubstituted; R₁, R₂, R₃ and R₄ are independently hydrogen, halogen,alkyl, aryl, heterocyclic, heteroaryl, silyl, fatty acid ester, acyloxy,aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A), —SOR_(A), —SO₂R_(A),—N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B), —NR_(A)R_(B),—C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or —N(R_(A))C(O)R_(B); eachof which is optionally substituted; or R₁ or R₂ may be covalently linkedto one of R₃ or R₄ to form a ring; each Q₁ and Q₂ are independentlyhydrogen, halogen, alkyl, aryl, heterocyclic, heteroaryl, silyl, fattyacid ester, acyloxy, aralkyl, —CN, —CF₃, —N₃, —NO₂, —OR_(A), —SR_(A),—SOR_(A), —SO₂R_(A), —N(R_(A))S(O₂)—R_(A), —N(R_(A))S(O₂)NR_(A)R_(B),—NR_(A)R_(B), —C(O)OR_(A), —C(O)R_(A), —C(O)NR_(A)R_(B), or—N(R_(A))C(O)R_(B); each of which is optionally substituted; R_(A) andR_(B) are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Z is absent whereinring A and ring B, to which Z is attached, are not connected; or Z is abridging group; n is 0, 1, or 2; m is 0, 1, or 2; and p is 0 or 1; or apharmaceutically acceptable salt, ester or hydrate thereof. 28-29.(canceled) 30-32. (canceled)
 33. A pharmaceutical composition comprisinga therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt, solvate or hydrate thereof thereof, incombination with a pharmaceutically acceptable carrier or excipient. 34.(canceled)
 35. A kit comprising an effective amount of a compound ofclaim 1 in unit dosage form, together with instructions foradministering the compound to a subject suffering from or susceptible toa viral disease.
 36. A method for identifying a protein which has itsexpression changed by a viral infection, the method comprising: a)treating a subject with a compound of claim 1 under conditions suitablefor modulation of the amount of the protein; and b) detecting modulationof the amount of the protein after treatment with the compound of claim1.